Experimental Models for Identifying Modifiers of Polyglutamine-Induced Aggregation and Neurodegeneration
2013
Huntington’s disease(HD) typifies a class of inherited neurodegenerative disorders in which a CAG expansion in a single gene leads to an extended
polyglutamine tractand misfolding of the expressed protein, driving cumulative neural dysfunction and degeneration. HD is invariably fatal with symptoms that include progressive neuropsychiatric and cognitive impairments, and eventual
motor disability. No curative therapies yet exist for HD and related polyglutamine diseases; therefore, substantial efforts have been made in the
drug discoveryfield to identify potential drug and drug target candidates for disease-modifying treatment. In this context, we review here a range of early-stage screening approaches based in in vitro, cellular, and invertebrate models to identify pharmacological and genetic modifiers of polyglutamine aggregation and induced neurodegeneration. In addition, emerging technologies, including high-content analysis, three-dimensional culture models, and
induced pluripotent stem cellsare increasingly being incorporated into
drug discoveryscreening pipelines for protein misfolding disorders. Together, these diverse screening strategies are generating novel and exciting new probes for understanding the disease process and for furthering development of therapeutic candidates for eventual testing in the clinical setting.
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